Apoptosis, or programmed cell death, is a principal mechanism by which organisms eliminate unwanted cells. The deregulation of apoptosis, either excessive apoptosis or the failure to undergo it, has been implicated in a number of diseases such as cancer, acute inflammatory and autoimmune disorders, ischemic diseases and certain neurodegenerative disorders (see generally Golstein (1998) Science 281: 1283-1312, and Ellis et al. (1991) Ann. Rev. Cell. Biol., 7: 663)
Caspases are a family of cysteine protease enzymes that are key mediators in the signaling pathways for apoptosis and cell disassembly (see, e.g., Thornberry (1998) Chem. Biol., 5: R97-R103). These signaling pathways vary depending on cell type and stimulus, but all apoptosis pathways appear to converge at a common effector pathway leading to proteolysis of key proteins. Caspases are involved in both the effector phase of the signaling pathway and further upstream at its initiation. The upstream caspases involved in initiation events become activated and in turn activate other caspases that are involved in the later phases of apoptosis.
The utility of caspase inhibitors to treat a variety of mammalian disease states associated with an increase in cellular apoptosis has been demonstrated using peptidic caspase inhibitors. For example, in rodent models, caspase inhibitors have been shown to reduce infarct size and inhibit cardiomyocyte apoptosis after myocardial infarction, to reduce lesion volume and neurological deficit resulting from stroke, to reduce post-traumatic apoptosis and neurological deficit in traumatic brain injury, to be effective in treating fulminant liver destruction, and to improve survival after endotoxic shock (see, e.g., Yaoita et al. (1998) Circulation, 97: 276-281; Endres et al. (1998) J. Cerebral Blood Flow and Metabolism, 18: 238-247; Cheng et al. (1998) J. Clin. Invest., 101: 1992-1999; Yakovlev et al. (1997) J. Neurosci. 17: 7415-7424; Rodriquez et al. (1996) J. Exp. Med., 184: 2067-2072; and Grobmyer et al. (1999) Mol. Med., 5: 585). Due to their peptidic nature, however, such inhibitors are typically characterized by undesirable pharmacological properties, such as poor cellular penetration and cellular activity, poor oral absorption, poor stability and rapid metabolism (see, e.g., Plattner and Norbeck (1990), Pp. 92-126 In: Drug Discovery Technologies, C. R. Clark and W. H. Moos, Eds. Ellis Horwood, Chichester, England, 1990). This has hampered their development into effective drugs.